Tag: Parasitology

Toxoplasma gondii, a parasite related to the one that causes malaria, infects about 30 percent of the world’s population. Most of those people don’t even know they are infected, but a small percentage develop encephalitis or ocular toxoplasmosis, which can lead to blindness. MIT biologist Jeroen Saeij and his colleagues are trying to figure out why some forms of the disease are so innocuous, while others ravage their victims. In their latest paper, they analyzed 29 strains of the parasite and found that some of those endemic to South America or atypical in North America provoke very strong inflammation in the cells they infect, which can severely damage tissue. “You have a lot of strains that are silent, and then you have these exotic strains that can cause very severe disease,” says Saeij, the Robert A. Swanson Career Development Associate Professor of Life Sciences. “The goal of the project was to see how different are these South American strains compared to strains that are really prevalent in North America and Europe.” Toxoplasma spores are found in dirt and easily infect farm animals such as cows, sheep, pigs, and chickens. Humans can be infected by eating undercooked meat or unwashed vegetables. Infection rates vary around the world: In the United States, it’s about 10 to 15 percent, while rates in Europe and Brazil are much higher, around 50 to 80 percent.

The strains that circulate most commonly in North America and Europe usually cause problems only in people with suppressed immune systems, such as AIDS patients or transplant recipients, although some atypical North American and European strains have been associated with severe ocular toxoplasmosis. It can also be dangerous for a woman to become infected while pregnant, as the parasite can cause birth defects. In South America, there is a much higher incidence of severe symptoms in otherwise healthy people. Scientists are still unsure what makes some South American strains so virulent, in part because most studies have focused on the North American and European varieties. In the new study, which appears this week in the journal PLoS Pathogens, Saeij and colleagues infected mouse immune cells known as macrophages with each of the 29 strains they had collected, representing global diversity. Macrophages are one of the parasite’s major targets and also a critical part of the host’s immune response. After infecting the cells, the researchers sequenced all of the messenger RNA molecules in the host cells. This reveals which genes — both parasite and host — are most active during infection.

Most strikingly, some South American and some atypical North American strains induced a type of immune reaction usually only seen during viral infection, known as the type 1 interferon response. This generates very strong inflammation in the host cells, which the researchers suspect may be causing the severe effects produced by those strains. Paradoxically, the parasite only sets off this immune response after the host cell has killed it, spilling the parasite’s DNA and RNA into the cell. “It’s often not the parasite that causes all the damage, but it’s actually the host immune response that’s causing most of the damage,” Saeij says. “We think that maybe what’s happening is these parasites come in and they trigger a hyperinflammatory host immune response that might cause damage to the eyes.” Toxoplasma is one of the few parasites that can infect any warm-blooded animal, says Mariane Melo, an MIT postdoc and the paper’s lead author. “For an organism to be able to infect any host and any cell, it needs to be able to have a very big arsenal of molecules that can function in the different hosts and the different cells,” Melo says. “However, we believe that different strains may have evolved to be able to maintain and reproduce optimally in a specific niche in nature, which may explain why different strains of Toxoplasma have such varying effects in different organisms.” She notes that a strain adapted to long-term survival in rats may cause a fatal infection in mice, or vice versa, because it might modulate host immune responses too much or not enough in hosts it is not optimally adapted to. The MIT researchers are now investigating why host cells kill certain South American strains so much more effectively, and why that killing provokes the interferon response. They have put their data, which includes gene expression profiles for all 29 strains, into a publicly available database for other researchers to use and add to. “There’s a lot of data, and we still understand very little of it,” Saeij says. “We hope that other people will now start studying more of these South American strains.”

Science Daily
January 21, 2014

Original web page at Science Daily

Behavioural changes persist after Toxoplasma infection is cleared. Mice infected with toxoplasmosis lose their instinctive fear for the smell of cats — and the parasite’s effects may be permanent. A parasite that infects up to one-third of people around the world may have the ability to permanently alter a specific brain function in mice, according to a study published in PLoS ONE. Toxoplasma gondii is known to remove rodents’ innate fear of cats. The new research shows that even months after infection, when parasites are no longer detectable, the effect remains. This raises the possibility that the microbe causes a permanent structural change in the brain. The microbe is a single-celled pathogen that infects most types of mammal and bird, causing a disease called toxoplasmosis. But its effects on rodents are unique; most flee cat odour, but infected ones are mildly attracted to it. This is thought to be an evolutionary adaptation to help the parasite complete its life cycle: Toxoplasma can sexually reproduce only in the cat gut, and for it to get there, the pathogen’s rodent host must be eaten. In humans, studies have linked Toxoplasma infection with behavioural changes and schizophrenia. One work found an increased risk of traffic accidents in people infected with the parasite; another found changes in responses to cat odour. People with schizophrenia are more likely than the general population to have been infected with Toxoplasma, and medications used to treat schizophrenia may work in part by inhibiting the pathogen’s replication.

Schizophrenia is thought to involve excess activity of the neurotransmitter dopamine in the brain. This has bolstered one possible explanation for Toxoplasma’s behavioural effect: the parasite establishes persistent infections by means of microscopic cysts that grow slowly in brain cells. It can increase those cells’ production of dopamine, which could significantly alter their function. Most other suggested mechanisms also rely on the presence of cysts. Research on Toxoplasma has mainly used the North American Type II strain. Wendy Ingram, a molecular cell biologist at the University of California, Berkeley, and her colleagues investigated the effects of two other major strains, Type I and Type III, on mouse behaviour. They found that within three weeks of infection with either strain, mice lost all fear of cat odour — showing that the behavioural shift is a general trait of Toxoplasma. More surprising was the situation four months after infection. The Type I pathogen that the researchers used had been genetically modified to provoke an effective immune response, allowing the mice to overcome the infection. After four months, it was undetectable in the mouse brain, indicating that no more than 200 parasite cells remained. “We actually expected that Type I wouldn’t be able to form cysts, and therefore wouldn’t be able to cause the behaviour change,” explains Ingram.

But that was not the case: the mice remained as unperturbed by cat odour as they had been at three weeks. “Long after we lose the ability to see it in the brain, we still see its behavioural effect,” says geneticist Michael Eisen, also at Berkeley. This suggests that the behavioural change could be due to a specific, hard-wired alteration in brain structure, which is generated before cysts form and cannot be reversed. The finding casts doubt on theories that cysts or dopamine cause the behavioural changes of Toxoplasma infections. Joanne Webster, a parasite epidemiologist at Imperial College London who co-discovered the fear-negating effects of Toxoplasma in rats, highlights the worrying implication that if the behavioural changes of Toxoplasma-caused schizophrenia are fixed, treatments that are intended to target cysts might have no effect. However, she notes that mice are not the best model for Toxoplasma infection in humans, because they experience more severe symptoms and complications. Webster uses rats in her research. Ingram says that her group is using mice because of the better genetic tools available to help to uncover the mechanism behind behavioural changes. However, she is not yet convinced of the link between Toxoplasma infections and schizophrenia. Her findings may actually weaken that link, because they seem to provide evidence against the dopamine hypothesis. She notes that Toxoplasma infections are common around the world, but their prevalence varies by region, whereas schizophrenia rates are consistent at around 1% globally.

Nature
October 1, 2013

Original web page at Nature

Like humans, mice can become infected with Borrelia. However, not all mice that come into contact with these bacteria contract the dreaded Lyme disease: Animals with a particular gene variant are immune to the bacteria, as scientists from the universities of Zurich and Lund demonstrate. Wild mice are the primary hosts for Borrelia, which are transmitted by ticks. Springtime spells tick-time. Lyme borreliosis is the most common tick-borne disease in Switzerland: around 10,000 people a year become infected with the pathogen. The actual hosts for Borrelia, however, are wild mice. Like in humans, the pathogen is also transmitted by ticks in mice. Interestingly, not all mice are equally susceptible to the bacterium and individual animals are immune to the pathogen. Scientists from the universities of Zurich and Lund headed by evolutionary biologist Barbara Tschirren reveal that the difference in vulnerability among the animals is genetic in origin.

Tschirren and colleagues examined wild mice for signs of a Borrelia infection in a large-scale field study. Borrelia afzelii — the scientific name for the bacteria — feed on mouse blood. The researchers discovered that mice with a particular variant of the antigen receptor TLR2 were around three times less susceptible to Borrelia. “The immune system of mice with this receptor variant recognizes the pathogen better and can trigger an immune response more quickly to destroy the Borrelia in time,” says Tschirren. Infected mice exhibit similar symptoms to humans — especially joint complaints. Consequently, in the wild infected mice probably do not survive for very long and weakened animals soon fall victim to foxes and birds of prey.

The protective gene variant is advantageous for its carriers and, according to the researchers, gradually becoming prevalent in the mouse population. Nonetheless, it is unlikely that all mice will one day be resistant to Borrelia. “The increasing resistance in the host is bound to lead to adaptations in Borrelia,” predicts Tschirren. “We can observe the evolutionary adaptation through the rearmament in mice and the pathogen.” People also have the antigen receptor TLR2, but not the resistant gene variant observed in mice. Whether the evolutionary arms race between mice and Borrelia will have repercussions for people remains to be seen. According to Tschirren, the bacterium does not necessarily have to become more aggressive for humans.

Science Daily
April 29, 2013

Original web page at Science Daily

Scientists from The University of Manchester have discovered that weight loss plays an important role in the body’s response to fighting off intestinal worms. The findings have been published in the journal PLOS Pathogens and show that the immune system hijacks the natural feeding pathways causing weight loss. This then drives the defense mechanisms down the correct pathway to expel the worms. Nearly one quarter of the world’s population is infected with gastrointestinal parasites. These prevalent infections often result in a period of reduced appetite resulting in weight loss. However, little is known about the factors controlling these feeding alterations and the reason why they occur. Scientists from the Manchester Immunology Group and the Institute of Inflammation and Repair studied the immune response system in mice that were lacking immune cells and feeding hormones. The mice were infected with the round worm parasite Trichinella spiralis. They identified that the mouse immune response to the parasite was behind two periods of reduced feeding through two distinct immune mediators. Interestingly, the immune system was using the hormone cholecystokinin, which usually stops feeding during daily meals to cause a reduction in weight and fat deposits. This then reduced the levels of the fat produced hormone leptin, which can influence the immune response.

To see if this reduction in leptin was beneficial, the researchers restored the leptin levels in the mice during the worm infection. They found that the treated mice did not make the correct immune response to the parasite resulting in a delayed worm expulsion. Dr John Worthington from the Faculty of Life Sciences carried out the research: “We were quite surprised by what we found during this study. Normally weight loss is associated with a negative immune response but this appears to suggest just the opposite that the immune driven weight loss was actually beneficial to the mouse’s ability to resolve an infection and get rid of the worm.” Dr Worthington continues: “Our study provides novel insights into how the immune system interacts with feeding pathways during intestinal inflammation. We hope it will help us to design new treatments for the many millions of people who suffer from parasitic infections of the gut.” Professor McLaughlin added: “This may also have relevance to why other human diseases causing inflammation of the digestive system affect appetite and nutrition.” The laboratories are currently expanding these studies to examine how other feeding hormones interact with the immune system during different infectious diseases.

Science Daily
February 5, 2013

Original web page at Science Daily

Toxoplasma is a common ‘cat parasite’, and has previously been in the spotlight owing to its observed effect on risk-taking and other human behaviours. To some extent, it has also been associated with mental illness. A study led by researchers from Karolinska Institutet in Sweden now demonstrates for the first time how the parasite enters the brain to influence its host. We believe that this knowledge may be important for the further understanding of complex interactions in some major public health issues, that modern science still hasn’t been able to explain fully,” says Antonio Barragan, researcher at the Center for Infectious Medicine at Karolinska Institutet and the Swedish Institute for Communicable Disease Control. “At the same time, it’s important to emphasize that humans have lived with this parasite for many millennia, so today’s carriers of Toxoplasma need not be particularly worried.” The current study, which is published in the scientific journal PLoS Pathogens, was led by Dr Barragan and conducted together with researchers at Uppsala University.

Toxoplasmosis is caused by the extremely common Toxoplasma gondii parasite. Between 30 and 50 per cent of the global population is thought to be infected, and an estimated twenty per cent or so of people in Sweden. The infection is also found in animals, especially domestic cats. People contract the parasite mostly by eating the poorly cooked flesh of infected animals or through contact with cat faeces. The infection causes mild flu-like symptoms in adults and otherwise healthy people before entering a chronic and dormant phase, which has previously been regarded as symptom-free. It is, however, known that toxoplasmosis in the brain can be fatal in people with depleted immune defence and in fetuses, which can be infected through the mother. Because of this risk, pregnant women are recommended to avoid contact with cat litter trays. A number of studies have been presented in recent years showing that the toxoplasmosis parasite affects its host even during the dormant phase. It has, for example, already been observed that rats become unafraid of cats and even attracted by their scent, which makes them easy prey. This has been interpreted as the parasite assuring its survival and propagation, since the consumed rat then infects the cat, which through its faces can infect the food that other rats might then proceed to eat. A number of studies also confirm that mental diseases like schizophrenia, depression and anxiety syndrome are more common in people with toxoplasmosis, while others suggest that toxoplasmosis can influence how extroverted, aggressive or risk-inclined an individual’s behaviour is.

“We’ve not looked at behavioural changes in people infected with toxoplasma, as that’s been dealt with by previous studies,” says Dr Barragan. “Instead, we’ve shown for the first time how the parasite behaves in the body of its host, by which I mean how it enters the brain and manipulates the host by taking over one of the brain’s neurotransmitters.” In one laboratory experiment, human dendritic cells were infected with toxoplasma. After infection, the cells, which are a key component of the immune defence, started secreting the signal substance GABA. In another experiment on live mice, the team was able to trace the movement of infected dendritic cells in the body after introducing the parasite into the brain, from where it spread and continued to affect the GABA system. GABA is a signal substance that, amongst other effects, inhibits the sensation of fear and anxiety. Disturbances of the GABA system are seen in people with depression, schizophrenia, bipolar diseases, anxiety syndrome and other mental diseases. “For toxoplasma to make cells in the immune defence secrete GABA was as surprising as it was unexpected, and is very clever of the parasite,” says Dr Barragan. “It would now be worth studying the links that exist between toxoplasmosis, the GABA systems and major public health threats.”

Science Daily
January 8, 2013

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The northeastern U.S. should prepare for a surge in Lyme disease this spring. And we can blame fluctuations in acorns and mouse populations, not the mild winter. So reports Dr. Richard S. Ostfeld, a disease ecologist at the Cary Institute of Ecosystem Studies in Millbrook, NY. What do acorns have to do with illness? Acorn crops vary from year-to-year, with boom-and-bust cycles influencing the winter survival and breeding success of white-footed mice. These small mammals pack a one-two punch: they are preferred hosts for black-legged ticks and they are very effective at transmitting Borrelia burgdorferi, the bacterium that causes Lyme disease. “We had a boom in acorns, followed by a boom in mice. And now, on the heels of one of the smallest acorn crops we’ve ever seen, the mouse population is crashing,” Ostfeld explains. Adding, “This spring, there will be a lot of Borrelia burgdorferi-infected black-legged ticks in our forests looking for a blood meal. And instead of finding a white-footed mouse, they are going to find other mammals — like us.”

For more than two decades, Ostfeld, Cary Institute forest ecologist Dr. Charles D. Canham, and their research team have been investigating connections among acorn abundance, white-footed mice, black-legged ticks, and Lyme disease. In 2010, acorn crops were the heaviest recorded at their Millbrook-based research site. And in 2011, mouse populations followed suit, peaking in the summer months. The scarcity of acorns in the fall of 2011 set up a perfect storm for human Lyme disease risk. Black-legged ticks take three bloodmeals — as larvae, as nymphs, and as adults. Larval ticks that fed on 2011’s booming mouse population will soon be in need of a nymphal meal. These tiny ticks — as small as poppy seeds — are very effective at transmitting Lyme to people. The last time Ostfeld’s research site experienced a heavy acorn crop (2006) followed by a sparse acorn crop (2007), nymphal black-legged ticks reached a 20-year high. The May-July nymph season will be dangerous, and Ostfeld urges people to be aware when outdoors. Unlike white-footed mice, who can be infected with Lyme with minimal cost, the disease is debilitating to humans. Left undiagnosed, it can cause chronic fatigue, joint pain, and neurological problems. It is the most prevalent vector-borne illness in the U.S., with the majority of cases occurring in the Northeast. Ostfeld says that mild winter weather does not cause a rise in tick populations, although it can change tick behavior. Adult ticks, which are slightly larger than a sesame seed, are normally dormant in winter but can seek a host whenever temperatures rise several degrees above freezing. The warm winter of 2011-2012 induced earlier than normal activity. While adult ticks can transmit Lyme, they are responsible for a small fraction of tick-borne disease, with spring-summer nymphs posing more of a human health threat. Past research by Ostfeld and colleagues has highlighted the role that intact forest habitat and animal diversity play in buffering Lyme disease risks. He is currently working with health departments in impacted areas to educate citizens and physicians about the impending surge in Lyme disease.

Science Daily
April 17, 2012

Original web page at Science Daily

University of Iowa researchers and colleagues have discovered how malaria manipulates the immune system to allow the parasite to persist in the bloodstream. By rescuing this immune system pathway, the research team was able to cure mice of bloodstream malaria infections. The findings, which were published Dec. 11 in the Advance Online Publication of the journal Nature Immunology, could point the way to a new approach for treating malaria that does not rely on vaccination and is not susceptible to the parasite’s notorious ability to develop drug resistance. “Malaria is chronic, prolonged infection and the host immune defense has a tough time clearing it and sometimes it never clears it,” says Noah Butler, PhD, UI postdoctoral research scholar and lead study author. “We’ve determined that this prolonged infection actually drives dysfunction of the immune cells that are supposed to be fighting the infection, which in essence allows further persistence of the parasite infection.” More specifically, the study showed that the malaria parasite stimulate these key immune cells (known as CD4+ T cells) so that they continuously express molecules called inhibitory receptors. Under normal circumstances, these molecules help to “apply the brakes” to the immune response and prevent over-activation that can be harmful. However, by keeping the mechanism turned on, the malaria parasite damps down the immune response significantly, reducing the T cells’ ability to fight the parasite and allowing it to persist.

Importantly, the team also showed that blocking the action of the inhibitory receptor molecules resulted in immediate and complete clearance of the malaria parasite. “When we blocked the function of these molecules, we took the brakes off the host’s immune response and everything got better — the overall immune response was dramatically improved and there was immediate control and accelerated clearance of the parasite,” says John Harty, PhD, professor of microbiology and pathology at the UI Carver College of Medicine and senior study author. “These findings suggest an alternative approach for the treatment of existing malaria infection.” More than half the world’s population is at risk of malaria, a mosquito-borne parasite that causes anemia and high fever and which can persist for weeks or months. There are more than 200 million cases of malaria each year and an estimated 800,000 children die from malaria annually. Harty notes that the current study was done in mice and it is not yet known if the same approach will work in humans. However, two factors suggest the strategy may have potential. First, drugs that block inhibitory receptor molecules are available and currently being tested as cancer therapies. And second, the UI team found that malaria infection in humans does lead to increased expression of inhibitory receptors on CD4+ T cells suggesting that these molecules could represent a viable target for human therapies.

Science Daily
January 10, 2012

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at Science Daily

They come out in the spring, and each year they spread further — the ticks. Thirty percent of them transmit borrelia pathogens, the causative agent of Lyme borreliosis that can damage joints and organs. The disease often goes undetected. In the future, a new type of gel is intended to prevent an infection — if applied after a tick bite. For years, Mrs. S. suffered from joint pain and headaches. After an odyssey through doctors’ waiting rooms, one doctor diagnosed Lyme borreliosis — an infectious disease transmitted by ticks. With its bite, the parasite introduced bacteria that then spread throughout the entire body. Mrs. S. is not alone — very often, the disease is recognized too late or not at all, or is not properly treated. Doctors are provided with no clues if the characteristic redness around the bite area is missing. Left untreated, Lyme borreliosis can cause symptoms that resemble rheumatism, damage joints, muscles and nerves and affect the organs.

If found in time, it can be successfully treated. If patients exhibit the disease-specific rash known as erythema migrans, doctors will prescribe antibiotics for several weeks. However, if, as in the case of Mrs. S., the disease has progressed far and is chronic, it is very difficult to treat. Currently, there is no prophylactic treatment and no vaccine against the infection. In the future, a new type of gel is supposed to nip the infection in the bud: the patient applies it locally immediately after the tick’s bite. Researchers of the Fraunhofer Institute for Cell Therapy and Immunology IZI in Leipzig developed the medication in close cooperation with the Swiss company Ixodes AG and the Institute for Infectious Diseases and Zoonoses of the Ludwig-Maximilian University in Munich (Institut für Infektionsmedizin und Zoonosen der LMU München). Ixodes AG is responsible for developing the formula, while IZI and LMU are carrying out the pre-clinical studies and the serological examinations.

“If the gel is applied immediately to the bite after the tick has been removed and one does not wait for any potential symptoms to show, Lyme borreliosis could be prevented. This is because during the first few days, the bacteria stay right around the spot where the tick bite occurred and spread out only after that. The active ingredient of the gel is azithromycin, which is highly effective against borrelia bacteria and kills them locally in the skin,” says Dr. Jens Knauer, project manager at IZI. Unlike other antibiotics, there is no known resistance of borrelia strains against azithromycin. Another advantage of the active ingredient: it has few side effects and as a result does not stress the body. It also distinguishes itself by its good depot action of up to five days in the tissue. The treatment is successful only if the medication is applied within the first few days after the tick’s bite. “This gel, however, cannot be used to treat an established infection; it is suitable only for prophylaxis,” emphasizes Dr. Knauer.

The pre-clinical studies have already been completed successfully; in mice, the gel was effective even five days after a tick’s bite. The application has been patented. Starting this past summer, in a clinical phase III study, the researchers are testing the medication on persons with proven tick bites. “Should the results of the pre-clinical studies be confirmed on humans, the gel will help to significantly lower the number of new infections,” the expert adds. Annually, up to 60,000 are stricken with Lyme borreliosis in Germany alone, according to estimates by the Robert Koch Institute, with an upward trend — since, due to climate change, ticks are expanding their range ever further. “As soon as the gel can be purchased at the pharmacy, persons who are particularly endangered, such as forest rangers, hunters, joggers or soccer players, should always carry it with them,” Knauer recommends.

Science Daily
January 10, 2012

Original web page at Science Daily

Researchers at the University of Gothenburg’s Sahlgrenska Academy have discovered a brand new tick-borne infection. Since the discovery, eight cases have been described around the world, three of them in the Gothenburg area, Sweden. In July 2009 a 77-year-old man from western Sweden was out kayaking when he went down with acute diarrhea, fever and temporary loss of consciousness. He was taken to hospital where it was found that he was also suffering with deep vein thrombosis (DVT). Following treatment with antibiotics, he was discharged some days later with an anticoagulant to thin his blood. However, the man — who had an impaired immune system — went down with a fever again. Over the following months the 77-year-old was admitted as an emergency case on several occasions, but despite repeated attempts to find a microbe, and repeated doses of antibiotics, the fever returned. Finally the patient’s blood underwent special analysis to look for bacterial DNA — and that produced results. The findings matched a bacterium in an online gene bank and the results were a sensation: the man had contracted a brand new infection in humans which had never been described in the world before.

The man’s blood contained DNA that derived with 100% certainty from the bacterium Neoehrlichia mikurensis. This bacterium was identified for the first time in Japan in 2004 in rats and ticks but had never before been seen in Sweden in ticks, rodents or humans. Christine Wennerås, a doctor and researcher at the Department of Infectious Diseases and the Department of Haematology and Coagulation at the University of Gothenburg’s Sahlgrenska Academy, has been studying the case since it first came to light. Last year she was able, for the first time, to describe the newly discovered disease in a scientific article published in the Journal of Clinical Microbiology. “Since our discovery the bacterium has been reported in eight cases around the world, three of them in Gothenburg,” says Wennerås. All three of the Gothenburg cases involved patients with an impaired immune system, all of whom became ill during the summer months when ticks are most active. “The nasty thing about this infection is that it causes DVT, at least in people with an impaired immune system,” says Wennerås. “This can be life-threatening. Fortunately, the infection can be treated successfully with antibiotics. “If the newly discovered bacterium is similar to those we already know, it has presumably spread from wild mammals to people via ticks, and it is unlikely that it can be passed on from person to person.” The mikurensis in the bacterium’s name comes from the Japanese island of Mikura, where it was first discovered.

Science Daily
January 10, 2012

Original web page at Science Daily